Von Willebrand's disease (vWD) is the most common inherited bleeding disorder and may occur in as many as 1 in 800 individuals. The von Willebrand factor (vWF) is heterogeneous multimeric plasma glycoprotein with two major functions. It facilitates platelet adhesion under conditions of high shear stress by linking platelet membrane receptors to vascular subendothelium. It also serves as the plasma carrier for factor VIII. The normal plasma level of vWF is 10 mg/L. The vWF activity is distributed among a series of plasma multimers with estimated molecular weights ranging from 400,000 to over 20 million. A single large vWF precursor subunit is synthesized in endothelial cells and megakaryocytes, where it is cleaved and assembled into the disulfide-linked multimers present in plasma, platelets, endothelial cells, and in the basement membrane of blood vessels. All of these pools of vWF contribute to the protein's main function, which is to promote attachment of platelets to areas of vessel injury. To optimize the availability of vWF at the site of injury, a highly active form of the protein is stored in secretory granules of platelets and of endothelial cells. When these cells sense tissue injury (e.g. by contact with thrombin) they instantly mobilize the stored vWF. The released vWF binds to glycoprotein Ib (GPIb) on the platelet surface and to components of the basement membrane, forming a bridge that can withstand high sheer stress of blood flow. VWF is necessary for this initial attachment of platelets to the injured area. Together with other adhesive proteins, such as fibrinogen, fibronectin, and thrombospondin, vWF interacts with the GPIIb/IIIa on activated platelets and contributes to platelet spreading and aggregation.
A modest reduction in plasma vWF concentration, or a selective loss in the high-molecular weight multimers, decreases platelet adhesion and causes clinical bleeding. Although vWD is heterogeneous, there are certain clinical features that are common to all the syndromes. With one exception (type III disease), all forms are inherited as autosomal dominant traits and affected patients are heterozygous with one normal and one abnormal vWF allele. In mild cases, bleeding occurs only after surgery or trauma. There are three major types of vWD. Patients with type I disease, the most common abnormality, have a mild to moderate decrease in plasma vWF. In the milder cases, although hemostasis is clearly impaired, the vWF level is just below the lower limit of normal, less than 5 mg/L. In type I disease, there is a parallel decrease in vWF antigen, factor VIII activity, and ristocetin cofactor activity, with a normal spectrum of multimers detected by sodium dodecyl sulfate (SDS)-agarose gel electrophoresis. Cultured endothelial cells derived from the umbilical cords of patients with vWD synthesize and secrete reduced quantities of vWF multimer and have a two- to fourfold reduction in vWF mRNA.
The variant forms of vWD (type II disease), which are much less common, are characterized by normal or near-normal levels of a dysfunctional vWF. Patients with the type IIa variant of vWD have a deficiency in the high- and medium molecular-weight forms of vWF multimer detected by SDS-agarose electrophoresis. This is due either to an inability to secrete the high-molecular-weight vWF multimets or to proteolysis of the multimers soon after they leave the endothelial cell and enter the circulation. The quantity of vWF antigen and the amount of associated factor VIII are usually normal. In the type IIb variant, there is also a loss in high-molecular-weight multimers. However, in type IIb disease, it is due to the inappropriate binding of vWF to platelets. This forms intravascular platelet aggregates that are rapidly cleared from the circulation, causing mild, cyclic thrombocytopenia.
Approximately 1 in 1 million individuals have a very severe form of vWD that is phenotypically recessive (type III disease). Type III patients are usually the offspring of two parents with mild type I disease. However, in many cases, the parents are very mildly affected or are asymptomatic. Type III patients may inherit a different abnormality from each parent (a doubly heterozygous or compound heterozygous state) or be homozygous for a single defect. Type III patients have severe mucosal bleeding, no detectable vWF antigen or activity, and may have sufficiently low factor VIII that they have occasional hemarthroses like mild hemophiliacs.
Prior art treatment of vWD depends on the symptoms and the underlying type of disease. One type of treatment involves the use of cryoprecipitate, a plasma fraction enriched in vWF, or factor VIII concentrates, which retain high-molecular-weight vWF multimers (HUMATE-P®, KOATE HS®). A second therapeutic option, which avoid the use of plasma is use of 1-desamino-8-D-arginine vasopressin (DDAVP), or desmopressin.
However, there are times when treating such patients with the above-described therapeutic agents produces less than satisfactory results, and hemorrhaging continues. Thus, there is a need to develop additional therapies for treating vWD.